Abstract 16914: The Role of G Protein-Coupled Receptor Kinase2 and β-Arrestins in Maladaptive Post-Infarction Ventricular Remodeling
Remote territory fibrosis following myocardial infarction (MI) is an important mechanism for the development of heart failure (HF). G protein-coupled receptor kinase-2 (GRK2) plays a key role in this process through uncoupling β-adrenergic receptor (β-AR) signaling in failing human cardiac fibroblasts (CF). β-arrestins are involved in β-AR uncoupling and have receptor-independent functions including activation of downstream signaling pathways that may be involved in CF-mediated fibrosis. This study investigates the role of GRK2 and β-arrestin in regulating CF biology in post-MI remodeling. Adult rats underwent LAD ligation to induce MI. There was a significant decline in LV function at 2 weeks post-MI which was present at 12 weeks by echo. Remote territory fibrosis increased 3-fold by 2 weeks post-MI progressing to 6-fold by 12 weeks, consistent with adverse remodeling. In LV CF isolated post-MI, collagen synthesis was upregulated over 2-fold by 2 weeks and remained elevated at 12 weeks post-infarct. β-arrestin expression was increased 2-fold and GRK2 activity was increased 1.4-fold at 12 weeks post-MI. This was associated with a 42% decrease in intracellular cAMP and loss of β-AR agonist-stimulated inhibition of collagen synthesis. Knockdown of β-arrestin in 8 week post-MI CF decreased myofibroblast transformation and collagen synthesis over 40% compared to scramble siRNA. Adenoviral-mediated expression of GRK2 inhibitor, GRK2ct, decreased isolated CF collagen synthesis by 40% versus Ad-Null at 12 weeks post-MI. Intra-aortic injection of Ad-GRK2ct immediately following LAD ligation decreased post-MI cardiac dysfunction; 25% greater fractional shortening at 6 weeks post-MI versus Ad-Null controls. Remote territory fibrosis occurs by 2 weeks post-MI and increases over time. Uncoupling of β-AR signaling via increased GRK2 and β-arrestin appears to be an important mechanism of increased myocardial fibrosis, as intracellular cAMP is known to inhibit collagen synthesis. Targeted inhibition of β-arrestin and/or GRK2 and restoration of β-AR signaling in CF may represent novel approaches to inhibiting pathological fibrosis and adverse remodeling post-MI.
- © 2013 by American Heart Association, Inc.